Research ArticleA Comparison of Fosaprepitant and Ondansetron forPreventing Postoperative Nausea and Vomiting in Moderate toHigh Risk Patients: A Retrospective Database Analysis

Chiaki Murakami, Nami Kakuta, Katsuyoshi Kume, Yoko Sakai, Asuka Kasai,Takuro Oyama, Katsuya Tanaka, and YasuoM. Tsutsumi

Department of Anesthesiology, Tokushima University, 3-18-15 Kuramoto, Tokushima 770-8503, Japan

Correspondence should be addressed to Yasuo M. Tsutsumi; tsutsumi@tokushima-u.ac.jp

Received 6 September 2017; Accepted 28 November 2017; Published 19 December 2017

Academic Editor: Giovanni Mariscalco

Copyright © 2017 Chiaki Murakami et al. This is an open access article distributed under the Creative Commons AttributionLicense, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properlycited.

Postoperative nausea and vomiting (PONV) occur in 30–50% of patients undergoing general anesthesia and in 70–80% of highPONV risk patients. In this study, we investigated the efficacy of fosaprepitant, a neurokinin-1 (NK1) receptor antagonist, comparedto ondansetron, a selective 5-hydroxytryptamine type 3 (5-HT3) receptor antagonist, in moderate to high PONV risk patientsfrom our previous randomized controlled trials. Patients (171 patients from 4 pooled studies) with the Apfel simplified score ≥2 and undergoing general anesthesia were randomly allocated to receive intravenous fosaprepitant 150mg (NK1 group, 𝑛 = 82)and intravenous ondansetron 4mg (ONS group, 𝑛 = 89) before induction of anesthesia. Incidence of vomiting was significantlylower in the NK1 group compared to the ONS group 0–2, 0–24, and 0–48 hours after surgery (2 versus 17%, 2 versus 28%, and 2versus 29%, resp.). However, no significant differences in PONV, complete response, rescue antiemetic use, and nausea score wereobserved between groups 0–48 hours after surgery. In moderate to high PONV risk patients, fosaprepitant decreased the incidenceof vomiting and was superior to ondansetron in preventing postoperative vomiting 0–48 hours after surgery.

1. Introduction

Postoperative nausea and vomiting (PONV) are distress-ing and serious adverse effects of anesthesia and surgery.PONV is experienced by 30–50% of patients undergoinggeneral anesthesia and up to 70–80% of high PONV riskpatients (female patients, nonsmokers, patients with historyof PONV and/or motion sickness, and receiving opioidspostoperatively [1–4]). In the “Consensus guidelines forthe management of postoperative nausea and vomiting”[4], use of antiemetics for PONV prophylaxis is recom-mended in moderate to high risk patients. Additionally, inpatients receiving prophylactic treatment for PONV, such asondansetron, a selective 5-hydroxytryptamine type 3 (5-HT3)receptor antagonist, PONV, occurs in up to 30–40% of thepatients during the first postoperative day [2, 5, 6]. In additionto patient distress and discomfort, PONV increases the riskof venous thrombus or pulmonary embolism, interferes with

physical therapy, and prolongs hospital stay [7–9]. Therefore,more effective therapies for preventing PONV are required,particularly in high risk patients.

Fosaprepitant is a water-soluble phosphorylated prodrugof aprepitant, a highly selective neurokinin-1 (NK1) recep-tor antagonist, and is rapidly transformed into aprepitantwhen administered intravenously [10]. Aprepitant blocksNK1 receptors and demonstrates antiemetic efficacy and along half-life, with two large trials finding aprepitant advanta-geous in preventing PONV, compared to ondansetron [11–13].Fosaprepitant is used for managing chemotherapy-inducednausea and vomiting (CINV) and was reported to havesuperior, longer-lasting effect in preventing CINV, comparedto other antiemetics [14].

Recently, we reported that fosaprepitant was more effec-tive than ondansetron in preventing vomiting 0–24 and0–48 h after surgery [15–17]. In this study, we collected datafrom our previous studies and evaluated the efficacy of

HindawiBioMed Research InternationalVolume 2017, Article ID 5703528, 5 pageshttps://doi.org/10.1155/2017/5703528

2 BioMed Research International

fosaprepitant in preventing PONV compared to ondansetronin moderate to high PONV risk patients.

2. Methods

This analysis was based on data from four identicallydesigned, double-blind, randomized, controlled studies.These studies were approved by the Human ResearchEthics Committee of the University of Tokushima (Tokush-ima, Japan) and registered in a clinical trials database(UMIN000008621, 000012999, 000007613, and 000018532).Written informed consent was obtained from all patients, andthe studies were conducted in accordance with the principlesoutlined in the Declaration of Helsinki.

Patients (aged 20–80 years) with the American Society ofAnesthesiologists (ASA) physical status of I–III and undergo-ing general anesthesia were enrolled in the studies. They allhad Apfel simplified score for PONV ≥ 2, which includes 4factors: female sex, history of PONV and/or motion sickness,nonsmoker smoking status, and postoperative opioids use.Patients with 0-1, 2, and 3-4 factors are considered to beat low, moderate, and high risk for PONV, respectively [2].Exclusion criteria were ASA physical status of IV, neuraldiseases, abnormal liver and/or renal function, and use ofother antiemetics. Patient data recorded included gender,history of PONV and motion sickness, and smoking status.

Patients were randomized and allocated to groups usingQuickcalcs software (Graph-Pad Inc., La Jolla, CA, USA).To ensure investigator blinding randomization schedule wasgenerated by a statisticianwhowas not involved in the clinicalstudy. On the day of surgery, patients were randomized tothe NK1 group, which received intravenous fosaprepitant(150mg) and the ONS group, which received intravenousondansetron (4mg). Antiemetics were infused over 30minby anesthesiologists before induction of anesthesia, followingapproved administration protocols.

Anesthesia was induced with remifentanil 0.3–0.5𝜇g/kg/min, propofol 1-2mg/kg, and rocuronium 0.8mg/kg to facil-itate endotracheal intubation. Anesthesia was maintainedwith propofol (target controlled infusion: 2–4𝜇g/ml) orvolatile anesthetics (sevoflurane 1-2% or desflurane 3-4%)in oxygen with air mixture, remifentanil, and fentanyl.Incremental doses of rocuronium were used as necessaryfor muscle relaxation, which was reversed by sugammadex2mg/kg at the end of surgery. A rescue antiemetic (10mgmetoclopramide) and/or analgesic were administered onpatient request.

The incidence of nausea and vomiting, complete responserate (no vomiting and no rescue antiemetic use), rescueantiemetic use, and severity of nausea were evaluated byblinded observers 2, 24, and 48 hours after surgery. Theseverity of nausea was estimated using the nausea score (0,absence of nausea; 1–3 mild, moderate, and severe nausea,resp.). Scores were evaluated by blinded observers, whodetermined the highest scores in each surveyed period andall adverse events during the first 48 hours after surgery wererecorded.

Statistical analyses were performed using Statistical Pack-age for Social Sciences (SPSS) software (version 22, SPSS

Table 1: Patient demographics.

NK1 group ONS groupPatients 𝑛 = 82 𝑛 = 89

Age, years 57 ± 14 56 ± 13

Height, cm 154 ± 8 155 ± 6

Weight, kg 57 ± 11 56 ± 10

ASA PS I/II/III 23/58/1 27/61/1PONV risk factors

Nonsmoker (𝑛) 80 88History of motion sickness (𝑛) 26 22Women (𝑛) 82 89Postoperative opioids, 𝜇g 470 ± 449 443 ± 451

Duration of anesthesia, min 269 ± 124 280 ± 138

Duration of surgery, min 209 ± 113 219 ± 129

Anesthetics; remifentanil, mg 3.4 ± 2.4 3.2 ± 3.2

Blood loss, ml 321 ± 488 251 ± 360

Fluid volume, ml 2245 ±1312

2127±1101

Data are presented as means ± SD (or range) or number of patients; NK1group, i.v. fosaprepitant; ONS group, i.v. ondansetron; PONV, postoperativenausea and vomiting; ASA PS, American Society of Anesthesiologistsphysical status.

INC., Chicago, IL, USA). Data are expressed as means ±standard deviations. 𝑃 values < 0.05 were considered statis-tically significant without any adjustment for multiplicity oftesting. 𝑇-test and 𝜒2 test were used for analyzing patientdemographics, cumulative incidence of vomiting at eachtime point, incidence of nausea, rescue antiemetic use, andcomplete response (no vomiting and no rescue) 0–2, 0–24,and 0–48 hours after surgery.TheMann–Whitney𝑈 test wasused to analyze nausea score at these time points.

3. Results

This study included 171 female patients with the Apfelsimplified score ≥ 2 (82 in the NK1 group and 89 in the ONSgroup). No significant differences in patient demographics,risk factors for PONV, duration of anesthesia and surgery,blood loss, and fluid volume were observed between thegroups (Table 1).

There was no significant difference in the percentage ofpatients with no vomiting and no rescue (complete response)at 0–2 hours (78 versus 80%, resp.; 𝑃 = 0.852), 0–24 hours (71versus 67%, resp.; 𝑃 = 0.741), and 0–48 hours (71 versus 67%,resp.; 𝑃 = 0.741) after surgery. However, the incidence ofvomiting was significantly lower in the NK1 group comparedto the ONS group at 0–2 hours (2 versus 17%, resp.; 𝑃 =0.0016), 0–24 hours (2 versus 28%, resp.; 𝑃 < 0.0001), and0–48 hours (2 versus 29%, resp.; 𝑃 < 0.0001) after surgery(Table 2). Where rates of vomiting were adjusted for use ofrescue antiemetic, both groupswere similar in terms of rescueantiemetic use for the 0–48 h interval. The rescue antiemeticwas administered 10mg metoclopramide when the patientsrequired postoperative rescue antiemetic. No statistically

BioMed Research International 3

Table 2: Postoperative parameters.

NK1 group, 𝑛 = 82 ONS group, 𝑛 = 89 𝑃 value0–2 hours

PONV 34 (41%) 25 (28%) 0.077Complete response 64 (78%) 71 (80%) 0.852Vomiting 2 (2%)∗ 15 (17%) 0.0016Rescue antiemetic use 18 13 0.238

0–24 hoursPONV 45 (55%) 44 (49%) 0.647Complete response 58 (71%) 60 (67%) 0.741Vomiting 2 (2%)∗ 25 (28%) <0.0001Rescue antiemetic use 30 26 0.331

0–48 hoursPONV 45 (55%) 47 (53%) 0.878Complete response 58 (71%) 60 (67%) 0.741Vomiting 2 (2%)∗ 26 (29%) <0.0001Rescue antiemetic use 30 29 0.631

Data are presented as number of patients (percentile); NK1 group, i.v. fosaprepitant; ONS group, i.v. ondansetron; PONV, postoperative nausea and vomiting.∗𝑃 <0.05 compared to ONS group.

Table 3: Nausea and NRS.

NK1 group,𝑛 = 82

ONS group,𝑛 = 89

0–2 hoursSeverity of nausea (0/1/2/3) 48/15/10/9 65/6/4/14

2–24 hoursSeverity of nausea (0/1/2/3) 62/10/6/4 57/10/10/12

24–48 hoursSeverity of nausea (0/1/2/3) 76/5/1/0 77/6/2/4

Data are presented as number of patients or median (interquartile range);NK1 group, i.v. fosaprepitant; ONS group, i.v. ondansetron; severity ofnausea: 0 = absence of nausea, 1 = mild nausea, 2 = moderate nausea, and3 = severe nausea.

significant differences in PONV, rescue antiemetic use, andnausea score were observed between the groups for anyanalyzed period (Tables 2 and 3).

4. Discussion

This study indicated that fosaprepitant is superior toondansetron in preventing vomiting 0–2, 0–24, and 0–48hours after surgery in moderate to high PONV risk patients.No significant differences were observed between fosaprepi-tant and ondansetron in incidence of PONV, completeresponse rate, use of rescue antiemetics, and severity ofnausea.

Several neurotransmitter receptor systems includingdopaminergic, cholinergic, histaminergic, serotonergic (5HT-2 and 5HT-3), and NK1 systems are associated with nauseaand vomiting [18]. 5HT-3 receptor antagonists and NK1receptor antagonists were shown to be effective in preventingCINV. A corticosteroid and a 5HT-3 receptor antagonist are

often combined for preventing CINV. Recently, NK1 recep-tor antagonists, aprepitant and fosaprepitant, have becomeavailable and their use has improved the management ofCINV [19]. In the 2016 update of MASCC/ESMO consensusguidelines, for prophylaxis of acute and delayed nausea andvomiting induced by chemotherapy, a combination of a 5-HT3 receptor antagonist, dexamethasone, and aNK1 receptorantagonist is recommended [20]. NK1 receptor antagonistsare expected to reduce the incidence of CINV.

NK1 receptor antagonist aprepitant was shown to beeffective in preventing PONV.Diemunsch et al. [12] suggestedthat aprepitant was significantly superior to ondansetron inpreventing vomiting. Gan et al. [11] showed that aprepitantwas as effective in reducing nausea as ondansetron and moreeffective in preventing vomiting during the first 24 and 48hours after surgery. Moreover, analysis of data from twoclinical trials [13] indicated that aprepitant was superior toondansetron in preventing PONV.

In this study, we used fosaprepitant, a prodrug of aprepi-tant. Fosaprepitant is converted to aprepitant within 30 min-utes of intravenous administration and blocks NK1 receptors.A dose of 115mg of fosaprepitant was reported equivalent to125mg of aprepitant [10], with intravenous administrationof 150mg of fosaprepitant showing the same efficacy as a3-day oral aprepitant treatment (125/80/80mg) [21]. In ourprevious studies [15–17], we demonstrated the efficacy offosaprepitant in preventing PONV in patients undergoinggeneral anesthesia compared to ondansetron. This studyenrolledmoderate to high PONV risk patients and confirmedfosaprepitant efficacy compared to ondansetron. Improvedefficacy of fosaprepitant in preventing postoperative vomitingmay be attributed to its long half-life.

For moderate to high PONV risk patients, multimodalprevention approaches can reduce the risk of PONV. Con-sensus guidelines for managing postoperative nausea and

4 BioMed Research International

vomiting [4] recommend an antiemetic combination ofdexamethasone (4mg) and ondansetron (4mg). Consideringthe superior antiemetic effect of fosaprepitant compared toondansetron in this study, a combination of dexamethasoneand fosaprepitant (instead of ondansetron) may be moreeffective. Moreover, long half-life of fosaprepitant suggeststhat a single administration of fosaprepitant may be equiv-alent or more effective than a combination dexamethasone-ondansetron treatment in preventing PONV. Further evalua-tion of clinical characteristics of fosaprepitant in combinationwith other antiemetics for PONV prevention is planned.

Certain limitations should be noted. Fosaprepitant has amuch longer half-life than ondansetron and, consequently,longer duration of activity, which may account for improvedprevention of vomiting. Additionally, as antiemetics areexpected to be more effective when administered towards theend of surgery compared to during induction of anesthesia,timing of drug administration could have affected our results.

Moreover, fosaprepitant treatment is relatively expensive,costing US$ 122.5 in Japan. However, as use of antiemeticscan reduce complications associated with PONV, preventingprolonged hospital stays, total medical costs may decrease.As we did not evaluate long-term outcomes in this study,it remains unclear whether reduction of postoperative vom-iting by fosaprepitant improves postoperative outcomes orprovides additional benefits for patients. Further studiesare required to evaluate the contribution of fosaprepitanttreatment to postoperative outcomes.

5. Conclusions

This study demonstrated that NK1 receptor antagonistfosaprepitant was superior to 5HT-3 receptor antagonistondansetron in preventing vomiting 0–2, 0–24, and 0–48hours after surgery in moderate to high PONV risk patients.However, no significant differences were observed betweenfosaprepitant and ondansetron in PONV incidence, completeresponse, use of rescue antiemetics, and nausea severity at anyperiod analyzed.

Conflicts of Interest

The authors declare that there are no conflicts of interestregarding the publication of this article.

Authors’ Contributions

C.Murakami andN. Kakuta contributed equally to this work.

Acknowledgments

This study was supported entirely by JSPSKAKENHI (Grantsnos. 16K16278 and 16K10940).

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